To understand brain function mechanistically, and thus to take principled approaches in repairing damaged brains, biomedical scientists face the daunting task of bridging the gap between the electrophysiological properties of single cells and the emergent properties of neuronal networks. The proposed experiments will help bridge this gap for a problem of great relevance in cognition and learning and memory: the cellular bases of the coherent theta rhythm in the hippocampus. The central hypothesis is that a particular class of hippocampal inhibitory interneurons, called oriens lacunosum-moleculare (O-LM) cells, plays a crucial role in amplifying the theta rhythm in vivo and generating theta-rhythmic activity in vitro. Proposed brain-slice experiments rely upon a recently developed real-time dynamic clamp system to study the integrative properties of O-LM cells and to immerse living neurons in computer-simulated microcircuits. Building such hybrid microcircuits-small brain circuits containing biological and simulated neurons that interact in real time- allows one to test precise hypotheses of microcircuit function with unprecedented quantitative rigor. Additional proposed studies focus on the consequences of O-LM-cell projections to the distal dendrites of pyramidal cells, as well as the consequences of O-LM-cell loss for the theta rhythm in vivo and in vitro. The proposed research program has five aims: (1) To study the input-output properties of O-LM cells in response to artificial synaptic barrages that mimic the in vivo state. (2) To study how phase-locked, distal and proximal inhibitory inputs can lead to phase-locked sparse firing in excitatory pyramidal cells. (3) To study the effects of distal O-LM-based inhibition on phase-dependent selection of dendritic inputs to pyramidal neurons. (4) To study how input from oriens-lacunosum moleculare (O-LM) interneurons to pyramidal cells and fast- spiking interneurons contributes to self-organized theta and gamma rhythms in closed-loop networks. (5) To study the importance of synchronization of O-LM cells for rhythmic activity under manipulation of feedback input, artificial rhythmic drive from the septum, and other factors. The long-term goal of this research program is to understand, with quantitative and mechanistic rigor, the mechanisms by which both normal and abnormal rhythmic behaviors emerge in the hippocampus and other cortical regions. The work will be immediately relevant to understanding the theta and gamma rhythms. These two patterns of coherent activity seem crucial for normal cognition and learning and memory, and are disrupted in a broad range of conditions including epilepsy, schizophrenia, Parkinson's disease, and Alzheimer's disease. Because the proposed approach can show how specific membrane mechanisms contribute to network function, it is particularly useful for identifying new drug targets. An added bonus of the proposed approach is that the dynamic clamp technology developed for these studies may prove useful for therapeutic, feedback-controlled electrical stimulation of the brain. PUBLIC HEALTH RELEVANCE: The proposed project is relevant to public health for two reasons. First, the proposed work allows rigorous study of rhythmic brain activity known to be important for cognition and learning and memory. Second, electronic technology being developed and used for this project will be valuable for feedback-based electrical stimulation of brain structures in neurological patients.